sCR1sLex ameliorates ischemia/reperfusion injury in experimental lung transplantation

Background: The nonspecific immune response with activation of the complement system and polymorphonuclear leukocytes is important for the mediation of reperfusion injury after lung transplantation, In this study, we investigated the combined blockade of the complement system and leukocyte adhesion by a novel drug combining soluble complement receptor type 1 (sCR1, CD35) with the selectin ligand sialyl Lewis X (sLe(X), CD15s) synthesized to sCR1sLe(X). Both sCR1 and sCR1Le(X) were supplied by AVANT Immunotherapeutics, Inc, Needham, Massachusetts. Methods: Orthotopic allogeneic single left lung transplantation was performed in male rats (Brown Norway to Fischer F334; n = 5 in all groups) after a total ischemic time of 20 hours. Recipients received either no specific treatment (control) or administration of sCR1 (10 mg/kg) or sCR1sLe(X) (10 mg/kg) 15 minutes before reperfusion by intracardiac injection, Twenty-four hours after reperfusion, the native contralateral lung was occluded to assess gas exchange of the graft only. In additional animals (5 per group), lung tissue was frozen 24 hours after reperfusion and assessed for myeloperoxidase activity as a measurement of neutrophil migration into the graft and thiobarbituric acid reactive substances to quantify lipid peroxidation. Results: Graft function as assessed by arterial Po-2 in recipients treated with sCR1sLeX was superior not only to that of controls (383 +/- 53 vs 56 +/- 7 mm Hg, P =.000095) but also to that of animals treated with sCR1 (243 +/- 35 mm Hg, P =.031). This improvement was confirmed by significant reduction of neutrophil migration (0.33 +/- 0.05 vs control, 1.0 +/- 0.09 Delta OD/mg/min, P =.0000024) and lipid peroxidation (6.2 +/- 0.38 vs control, 10.6 +/- 0.53 pmol/g, P =.00021). Conclusions: Our data indicate that combined inhibition of complement activation and leukocyte adhesion with sCR1sLe(X) reduces reperfusion injury significantly and that both mechanisms are effectively inhibited in this model.